Zinc supplements have been shown to reduce the duration and severity of watery diarrhea in studies around the globe, but its mode of action is not known. Initially it was believed that zinc was acting to correct or ameliorate zinc deficiency, but this appears not to be the only means of protection because children and animals who are not zinc deficient still benefited from zinc in studies of diarrhea. We hypothesized that zinc would have beneficial effects on infection with a common pathogen, enteropathogenic Escherichia coli (EPEC), and tested this hypothesis in preliminary experiments. Zinc at 1 mM concentration prevented the fluid secretory response observed when rabbit EPEC strains were inoculated into rabbit intestinal loops for 18 hours. In addition, similar concentrations of zinc abolished the ability of EPEC to adhere to human cells in tissue culture assays, and markedly reduced the expression of a bacterial protein, or adhesin, that EPEC use to adhere to human cells, the bundle-forming pilus. Zinc also inhibits a key enzyme involved in the conversion of 5'-AMP to adenosine in the lumen of the intestine, called ecto-5'-nucleotidase, and reduces the secretory response to AMP when tested in the Ussing chamber, an electrophysiology device for measuring the flow of fluid and electrolytes into the intestine. We conclude that zinc has direct effects on EPEC bacteria which interfere with their ability to adhere and cause disease. In addition, zinc also has direct effects on the signaling and secretory pathways in the gut which are activated by EPEC bacteria and trigger watery diarrhea. These effects should be considered pharmacologic effects of zinc, not zinc replacement therapy, since they occur in the absence of zinc deficiency and may require doses of zinc above those needed for nutrition. The goals of this project are to determine if other EPEC gene products are inhibited by zinc, determine which enzymes and ion channels in the human Gl tract are the most likely targets of zinc, determine if adenine nucleotide secretion into the gut lumen is an important mechanism in EPEC-induced diarrhea, and determine if short treatments with zinc can prevent illness in rabbits infected with a rabbit EPEC strain, and if zinc supplements can treat established infection with rabbit EPEC.